Iontophoresis, according to Dorland's Illustrated Medical Dictionary, is defined to be "the introduction, by means of electric current, of ions of soluble salts into the tissues of the body for therapeutic purposes." Iontophoretic devices have been known since the early 1900's. British patent specification No. 410,009 (1934) describes an iontophoretic device which overcame one of the disadvantages of such early devices known to the art at that time, namely the requirement of a special low tension (low voltage) source of current which meant that the patient needed to be immobilized near such source. The device of that British specification was made by forming a galvanic cell from the electrodes and the material containing the medicament or drug to be delivered transdermally. The galvanic cell produced the current necessary for iontophoretically delivering the medicament. This ambulatory device thus permitted iontophoretic drug delivery with substantially less interference with the patient's daily activities.
More recently, a number of United States patents have issued in the iontophoresis field, indicating a renewed interest in this mode of drug delivery. For example, U.S. Pat. No. 3,991,755 issued to Vernon et al; U.S. Pat. No. 4,141,359 issued to Jacobsen et al; U.S. Pat. No. 4,398,545 issued to Wilson; and U.S. Pat. No. 4,250,878 issued to Jacobsen disclose examples of iontophoretic devices and some applications thereof. The iontophoresis process has been found to be useful in the transdermal administration of medicaments or drugs including lidocaine hydrochloride, hydrocortisone, fluoride, penicillin, dexamethasone sodium phosphate, insulin and many other drugs. Perhaps the most common use of iontophoresis is in diagnosing cystic fibrosis by delivering pilocarpine salts iontophoretically. The pilocarpine stimulates sweat production; the sweat is collected and analyzed for its chloride content to detect the presence of the disease.
In presently known iontophoretic devices, at least two electrodes are used. Both of these electrodes are disposed so as to be in intimate electrical contact with some portion of the skin of the body. One electrode, called the active or donor electrode, is the electrode from which the ionic substance, medicament, drug precursor or drug is delivered into the body by iontophoresis. The other electrode, called the counter or return electrode, serves to close the electrical circuit through the body. In conjunction with the patient's skin contacted by the electrodes, the circuit is completed by connection of the electrodes to a source of electrical energy, e.g., a battery. For example, if the ionic substance to be delivered into the body is positively charged (i.e., a cation), then the anode will be the active electrode and the cathode will serve to complete the circuit. If the ionic substance to be delivered is negatively charged (i.e., an anion), then the cathode will be the active electrode and the anode will be the counter electrode.
Alternatively, both the anode and cathode may be used to deliver drugs of opposite charge into the body. In such a case, both electrodes are considered to be active or donor electrodes. For example, the anode can deliver a positively charged ionic substance into the body while the cathode can deliver a negatively charged ionic substance into the body.
It is also known that iontophoretic delivery devices can be used to deliver an uncharged drug or agent into the body. This is accomplished by a process called electroosmosis. Electroosmosis is the volume flow of a liquid (e.g., a liquid containing the uncharged drug or agent) through the skin induced by the presence of an electric field imposed across the skin.
Furthermore, existing iontophoresis devices generally require a reservoir or source of the beneficial agent (which is preferably an ionized or ionizable agent or a precursor of such agent) to be iontophoretically delivered or introduced into the body. Examples of such reservoirs or sources of ionized or ionizable agents include a pouch as described in the previously mentioned Jacobsen U.S. Pat. No. 4,250,878, or a pre-formed gel body as described in Webster U.S. Pat. No. 4,382,529 and Ariura et al. U.S. Pat. No. 4,474,570, which patents are incorporated herein by reference. Such drug reservoirs are electrically connected to the anode or the cathode of an iontophoresis device, or optionally to an electrolyte reservoir or an ion selective membrane, to provide a fixed or renewable source of one or more desired agents. See for example Parsi U.S. Pat. No. 4,731,049, incorporated herein by reference.
It is desirable to minimize the internal electrical resistance of an iontophoretic delivery device since this allows the device to be powered by a lower voltage, and therefore, less expensive, power source. One way of minimizing the internal electrical resistance of the device is to establish good electrical contact between the various components (e.g., the electrode, the drug reservoir, any electrolyte reservoir and any selectively permeable membrane) of the device as well as to establish good electrical contact between the device and the body surface (e.g., the skin or a mucosal membrane) through which the drug is to be delivered. Along with establishing an interface for ionic and/or water soluble species to diffuse, intimate contact between the delivery surface of the device and the body also ensures uniform electrical current distribution, thereby avoiding high localized current densities which could cause damage to body tissue.
Important criteria for adhesive compositions utilized as in-line contact adhesives for iontophoretic delivery devices in general, are: sufficient adhesion allowing prolonged adhesion to a body surface and allowing easy removal from the body surface without damaging the tissue, cohesion, bio- and chemical-compatibility, rapid drug transportability, and mechanical flexibility. When drugs are administered by electrotransport means rather than by passive diffusion, the adhesive should exhibit low resistance to drug transport and should contain minimal extraneous ions which could undesirably compete with the drug for delivery into the body.
The use of electrically-conductive adhesives in electrodes is known in the art. See U.S. Pat. No. 4,008,721, (vinyl acrylic copolymer which is activated by acetone or a low molecular weight alcohol); U.S. Pat. No. 4,391,278; (polymerized 2-acrylamido-2-methylpropanesulfonic acid); U.S. Pat. No. 4,274,420; (karaya gum having an ionizable salt or a finely powdered metal dispersed therethrough); and U.S. Pat. No. 4,566,762 (cross-linked latex polymers containing an electrically conductive aqueous phase). While these adhesives are suitable for conducting current, they are not well suited for allowing agent or electrolyte (e.g., drug ions and/or electrolyte ions) to be transported therethrough. In addition, the solvent used in the adhesive may react adversely with the drug or hinder the delivery of drug to the body, or constituents incorporated in the adhesive may interfere with or compete with the agent or electrolyte for transport into the body.
Others have attempted to use self-adhering matrices comprised of a gel formed from a hydrophilic natural or synthetic material such as a natural resinous polysaccharide, plasticized with water and/or polyols. See U.S. Pat. Nos. 4,474,570 and 4,706,680.
This invention therefore provides an adhesive formulation which overcomes many of the disadvantages associated with state of the art adhesives and is particularly suited for use as an in-line contact adhesive used to (1) adhere an iontophoretic delivery device to a body surface such as skin or a mucosal membrane and/or (2) to adhere together two or more elements of an iontophoretic delivery device electrode assembly, through which elements drug and/or electrolyte ions must travel.
It is an object of this invention to provide an adhesive formulation suitable for use as an in-line contact adhesive for electrically assisted drug delivery systems.
It is a further object of this invention to provide an adhesive which has an acceptably low resistance to ionic transport when in a hydrated state.
It is a still further object of this invention to provide such an adhesive having uniform charge distribution properties.